[D66] The serotonin theory of depression: a systematic umbrella review of the evidence

[René Oudeweg]

(De genadeslag voor de psychiatrie...)


https://www.nature.com/articles/s41380-022-01661-0

    Systematic Review
    Open Access
    Published: 20 July 2022

The serotonin theory of depression: a systematic umbrella review of the
evidence

    Joanna Moncrieff, Ruth E. Cooper, Tom Stockmann, Simone Amendola,
Michael P. Hengartner & Mark A. Horowitz

Molecular Psychiatry (2022)Cite this article

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nature.com
The serotonin theory of depression: a systematic umbrella review of the
evidence
Horowitz, Mark A.
51-65 minutes
Abstract

The serotonin hypothesis of depression is still influential. We aimed to
synthesise and evaluate evidence on whether depression is associated
with lowered serotonin concentration or activity in a systematic
umbrella review of the principal relevant areas of research. PubMed,
EMBASE and PsycINFO were searched using terms appropriate to each area
of research, from their inception until December 2020. Systematic
reviews, meta-analyses and large data-set analyses in the following
areas were identified: serotonin and serotonin metabolite, 5-HIAA,
concentrations in body fluids; serotonin 5-HT1A receptor binding;
serotonin transporter (SERT) levels measured by imaging or at
post-mortem; tryptophan depletion studies; SERT gene associations and
SERT gene-environment interactions. Studies of depression associated
with physical conditions and specific subtypes of depression (e.g.
bipolar depression) were excluded. Two independent reviewers extracted
the data and assessed the quality of included studies using the
AMSTAR-2, an adapted AMSTAR-2, or the STREGA for a large genetic study.
The certainty of study results was assessed using a modified version of
the GRADE. We did not synthesise results of individual meta-analyses
because they included overlapping studies. The review was registered
with PROSPERO (CRD42020207203). 17 studies were included: 12 systematic
reviews and meta-analyses, 1 collaborative meta-analysis, 1
meta-analysis of large cohort studies, 1 systematic review and narrative
synthesis, 1 genetic association study and 1 umbrella review. Quality of
reviews was variable with some genetic studies of high quality. Two
meta-analyses of overlapping studies examining the serotonin metabolite,
5-HIAA, showed no association with depression (largest n = 1002). One
meta-analysis of cohort studies of plasma serotonin showed no
relationship with depression, and evidence that lowered serotonin
concentration was associated with antidepressant use (n = 1869). Two
meta-analyses of overlapping studies examining the 5-HT1A receptor
(largest n = 561), and three meta-analyses of overlapping studies
examining SERT binding (largest n = 1845) showed weak and inconsistent
evidence of reduced binding in some areas, which would be consistent
with increased synaptic availability of serotonin in people with
depression, if this was the original, causal abnormaly. However, effects
of prior antidepressant use were not reliably excluded. One
meta-analysis of tryptophan depletion studies found no effect in most
healthy volunteers (n = 566), but weak evidence of an effect in those
with a family history of depression (n = 75). Another systematic review
(n = 342) and a sample of ten subsequent studies (n = 407) found no
effect in volunteers. No systematic review of tryptophan depletion
studies has been performed since 2007. The two largest and highest
quality studies of the SERT gene, one genetic association study
(n = 115,257) and one collaborative meta-analysis (n = 43,165), revealed
no evidence of an association with depression, or of an interaction
between genotype, stress and depression. The main areas of serotonin
research provide no consistent evidence of there being an association
between serotonin and depression, and no support for the hypothesis that
depression is caused by lowered serotonin activity or concentrations.
Some evidence was consistent with the possibility that long-term
antidepressant use reduces serotonin concentration.